Submissions for variant NM_177924.5(ASAH1):c.1085C>G (p.Pro362Arg)

dbSNP: rs1588973237

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Medical Affairs, Dicerna Pharmaceuticals	RCV001003328	SCV001161413	pathogenic	Farber lipogranulomatosis	2019-06-19	criteria provided, single submitter	literature only	Variant c.1085C>G is pathogenic given the following rationale. There are 2 unrelated patients who have been diagnosed with Farber disease as defined by Gene Reviews (https://www.ncbi.nlm.nih.gov/books/NBK488189/) who carry variant c.1085C>G. The first patient was described by Li et al., 1999, DOI: 10.1006/geno.1999.5940. Homozygous c.1085C>G variants were identified in the ASAH1 gene in this patient and acid ceramidase activity of <5% was confirmed through FLAG-tagged human AC cDNA expression in COS-1 cells. The second patient described by Dyment et al., 2014, doi: 10.1111/cge.12307, was diagnosed with Farber disease. Compound heterozygous for variants in the ASAH1 gene, c.648+1G>C and c.1085C>G, were revealed through genetic analysis. In this patient, immunoblot of acid ceramidase demonstrated negligable alpha-subunit was present. The Farber disease phenotype and functional testing in both studies indicate this variant is pathogenic resulting in the Farber disease phenotype.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001860537	SCV002256107	likely pathogenic	not provided	2023-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 362 of the ASAH1 protein (p.Pro362Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Farber disease (PMID: 10610716, 24164096, 32449975). ClinVar contains an entry for this variant (Variation ID: 812498). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ASAH1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ASAH1 function (PMID: 10610716, 23681708, 29379059). This variant disrupts the p.Pro362 amino acid residue in ASAH1. Other variant(s) that disrupt this residue have been observed in individuals with ASAH1-related conditions (PMID: 24355074), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.